The long-term objective of this application is to understand the roles and mechanisms of caspase-11 in regulating patho-physiological processes. Caspase-11, originally named ICH-3, is a member of the caspase-1 subfamily of cysteine proteases. Caspase-11 has been shown to play critical roles in innate immune responses by regulating cytokine maturation and in apoptosis. Recently it was found that caspase- 11 also plays an important role in regulating cell migration during acquired immune responses. Thus, caspase-11 may serve as a novel link between innate and acquired immune responses. This proposal is to explore the mechanism by which caspase-11 regulates cell migration and the mechanism that specifies the activation of different downstream pathways of caspase-11 in patho-physiological responses. The Specific Aim I is to elucidate the molecular mechanism by which caspase-11 regulates activated lymphocyte and macrophage migration in immune responses. This is to determine if caspase-11 regulates cell migration through a cell autonomous mechanism by regulating levels of key signal transduction molecules or cell non- autonomous mechanism by regulating key cytokine secretion. The Specific Aim II is to determine the molecular mechanism of caspase-11 activation and specification in regulating cytokine release, activated immune cell migration and apoptosis. The hypothesis is that caspase-11 exists in different protein complexes in a concentration, time or cell type-dependent manner during immune and inflammatory responses depending on the levels of caspase-11 and the interacting proteins that dictate whether to activate apoptosis, cytokine release or limit lymphocyte migration. The Specific Aim III is to determine the molecular mechanism of caspase-11 induction. The expression of caspase-11 may be regulated by NF-kB and STAT1 pathways. This Specific Aim will test the hypothesis that STAT1 regulates the basal expression of caspase-11 which is required for the induction of caspase-11, while the latter is regulated mainly through the NF-kB pathway. These studies will provide new molecular insights into the mechanism by which innate immune response participates in acquired immune responses and create new therapeutic options for infectious and autoimmune diseases. This work will also provide novel insights into the non-apoptotic function of caspases which are directly relevant for development of caspase inhibitors as drugs for treatment of human diseases.